Nanoscale particles having an iron oxide-containing core enveloped by at least two shells

ABSTRACT

The invention relates to nanoscale particles suited especially for use in tumor therapy by hyperthermia. Said particles comprise a (preferably superparamagnetic) iron oxide-containing core and at least two shells surrounding said core. The (innermost) shell adjoining the core is an envelope which comprises groups capable of forming cationic groups and is broken down by human or animal tissue at such a slow rate as to allow for association of the core surrounded by said envelope with the surface of cells and/or for absorption of said core into the inside of cells. The outer shell(s) consist(s) of species having neutral and/or anionic groups which allow the nanoscale particles to appear to the outside as having a neutral or negative charge and which are broken down by human or animal tissue more rapidly than the innermost shell—and in so doing uncover the shells underneath—but still sufficiently slowly so as to ensure that the nanoscale particles are adequately distributed in a tissue infiltrated with same particles in a particular point.

[0001] The present invention relates to nanoscale particles having aniron oxide-containing, ferri-, ferro- or (preferably) superparamagneticcore and at least two shells surrounding said core. Said particles maybe used for medical purposes, particularly for tumor therapy byhyperthermia.

[0002] It is generally believed that in comparison to their benigncounterparts, transformed cells (cancer cells) of most tumors have ahigher phagocytosis activity. Reasons therefor are considered to be theinvasive activity into adjacent tissues and the exocytosis of lyticenzymes associated therewith as well as a higher metabolic activity ofsaid transformed cells. In striving for a more rapid cellularproliferation the cancer cells dedifferentiate and thereby lose part oftheir specifity towards normal signal transduction pathways and,generally towards transmembrane processes. Most recently such changeshave been recognized by, e.g., the loss/mutation of the important celladhesion proteins and glycoproteins of the cell surface which meanwhileare considered to represent one of the prerequisites for theuncontrolled growth of malignant cells. Thus it is known that likemacrophages, cancer cells incorporate fragments of normal cells or ofother cell debris and can endogenously convert them into utilizablenutrients inside lysosomes. The signal recognition by which theendocytosis process is initiated in tumor cells is still not clear onprinciple. However, from in vivo studies on intralesionally appliedparticle suspensions it can be inferred that the distribution within thetissue and the incorporation into tumor cells is mainly dependent on thesize and the charge of the particles. In orientation studies the presentinventors have observed that with neutrally to negatively chargedparticles the distribution within the tumor tissue (e.g. of thecarcinoma of the mamma) into the interstitial space of the tissue(microcapillaries, septa, lobuli) is very high. If the distribution ofsuch particles is promoted by heat the process of uniform distributioneven is significantly enhanced. It is assumed that neutral to negativelycharged particles interact only weakly with the extracellular receptormolecules and the glycokalyx. The explanation therefor are the much morefrequently negatively charged ion channels and integral proteins on thesurfaces of the cells. Almost always positively charged ions that serveeither the signal transduction (e.g. in the case of Ca²⁺) or themaintenance of the osmotic equilibrium (e.g. Na⁺, K⁺) are imported. Therather more unspecific incorporation takes place via positively chargedgroups of extracellular particles since in that case the cell can importutilizable biomolecules in most cases. Furthermore biogenous sugars arealso recognized and imported, said importation being less specific withtumor cells due to dedifferentiated receptor molecules. Owing to highermetabolic activity and the frequently existing deficient oxygen supplyof the tumor tissues, the tumor cell must furthermore conduct ananaerobic glycolysis to a much higher extent than normal cells, which inpart also results in an excessive acidification of the tumor environmentdue to accumulation of lactate. A further result thereof is, however,also that due to the much lower energy yield of the anaerobic metabolicpathways the tumor cells consume much more substrate of high energycontent which substrate therefore has to be imported into the cells inhigh amounts. Since endocytosis as such also is an energy consumptiveprocess, the tumor cell is under time pressure: although by higherimportation rates more substrate is imported, also much low-gradematerial is taken in that affords hardly any energy yield later.Additionally, the continuous division and synthesis processes consume somuch energy that in this case the usually strictly controlled intake ofmaterials from the surrounding environment would not be sufficient and alarge part of the cells would die. Therefore it makes sense that thetumor cell has a survival edge with a high unspecific intracellularintake since it can certainly gain more energy more rapidly from thedigestion of “raw” elements than in the case of the highly selectiveintake of fewer, more specific elements.

[0003] Through observations in cell cultures and in experimental tumorsthe present inventors have found that the intracellular incorporationrate of (highly) positively charged particles into tumor cells is up to1000 times higher than that of comparable particles with neutral ornegative surface charge. This is attributed to the high affinity of thepositive charges of the particles towards the many negatively chargedintegral proteins and receptors on the cell surface. When observing ashorter period of time, e.g., 6 to 48 hours the tumor cells which aremore active with respect to metabolism and division take in much higheramounts of such particles than normal cells, even with the affinity ofthe particles towards the surfaces of the normal cells being the same.If additionally the lower intake specifity of the tumor cells is takeninto account there is a substantial overall difference in cellularintake which in theory should be exploitable for therapeutic purposes.For said purpose no systemic enrichment is necessary, but merely askillful exploitation of surface charges for the adhesion of theparticles to the cell surfaces of the tumor cells.

[0004] Particles having the highest achievable external positive chargebecome electrostatically bound to the cells within a few seconds and inthe case of tumor cells they are also internalized within only 2 to 6hours in such amounts that already by means of the intracellularproportion of the (nano-) particles alone compact cell pellets can beheated (to 45-47° C.) and deactivated in vitro by an externalalternating magnetic field. However, in vivo a very poor distribution ofsuch (highly) positively charged particles within the tissue is found.In comparison thereto, neutral or negatively charged particles show abetter distribution within the tissue but become less well imported intothe cells and are predominantly transported away by the RES instead.Thus, for example, studies with dextran-coated magnetite particles haveshown that the dextran was degraded endogenously and thereby an optimumenergy intake inside the tumor cells was prevented. The presentinventors have furthermore found that even though magnetite particlesprovided with a coating having positive charges (e.g. based onaminosilane) were not degraded endogenously they showed a poordistribution within the tissue. It would therefore be desirable to haveavailable particles which combine the properties of the two (magnetite)particles just described, i.e., on the one hand show a very gooddistribution within the tumor tissue and on the other hand are alsoincorporated well by the tumor cells.

[0005] According to the present invention it has now been found thatsuch particles can be obtained by providing a (preferablysuperparamagnetic) iron oxide-containing core with at least two shells(coats), the shell adjacent to the core having many positively chargedfunctional groups which permits an easy incorporation of the thusencased iron oxide-containing cores into the inside of the tumor cells,said inner shell additionally being degraded by the (tumor) tissue atsuch a low rate that the cores encased by said shell have sufficienttime to adhere to the cell surface (e.g. through electrostaticinteractions between said positively charged groups and negativelycharged groups on the cell surface) and to subsequently be incorporatedinto the inside of the cell. In contrast thereto, the outer shell(s) is(are) constituted by species which shield (mask) or compensate,respectively, or even overcompensate the underlying positively chargedgroups of the inner shell (e.g. by negatively charged functional groups)so that, from without, the nanoscale particle having said outer shell(s)appears to have an overall neutral or negative charge. Furthermore theouter shell(s) is (are) degraded by the body tissue at a (substantially)higher rate than the innermost shell, said rate being however still lowenough to give the particles sufficient time to distribute themselveswithin the tissue if they are injected punctually into the tissue (e.g.in the form of a magnetic fluid). In the course of the degradation ofsaid outer shell(s) the shell adjacent to the core is exposed gradually.As a result thereof, due the outer shell(s) (and their electroneutralityor negative charge as seen from the exterior) the coated cores initiallybecome well distributed within the tissue and upon their distributionthey also will be readily imported into the inside of the tumor cells(and first bound to the surfaces thereof, respectively), due to theinnermost shell that has been exposed by the biological degradation ofthe outer shell(s).

[0006] Thus, the present invention relates to nanoscale particles havingan iron oxide-containing core (which is ferro-, ferri- or, preferably,superparamagnetic) and at least two shells surrounding said core, the(innermost) shell adjacent to the core being a coat that features groupscapable of forming cationic groups and that is degraded by the human oranimal body tissue at such a low rate that an association of the coresurrounded by said coat with the surfaces of cells and the incorporationof said core into the inside of cells, respectively is possible, and theouter shell(s) being constituted by species having neutral and/oranionic groups which, from without, make the nanoscale particles appearneutral or negatively charged and which is (are) degraded by the humanor animal body tissue to expose the underlying shell(s) at a rate whichis higher than that for the innermost shell but still low enough toensure a sufficient distribution of said nanoscale particles within abody tissue which has been punctually infiltrated therewith.

[0007] Preferably the substance for the core consists of pure ironoxide, particularly magnetite or maghemite (γ-Fe₂O₃). Examples of othersubstances for the core that may be employed according to the presentinvention are other pure iron oxides but also mixed oxides containingiron such as, e.g., those of the general formula Me(II)Fe₂O₄ whereinMe(II) is preferably Zn, Cu, Co, Ni or Mn (in the case of Me(II)=Fe theresult is magnetite). Furthermore metals different from the above metalsmay also be present in the cores, for example alkaline earth metals suchas Ca and Mg. Generally, the concentration of metal atoms different fromiron atoms in the substance for the core is preferably not higher than70, and particularly not higher than 35 metal atom-%. It is preferred,however that said iron oxide particles be pure iron oxide particles andparticularly those which contain both Fe(III) and Fe(II), the ratioFe(II)/Fe(III) ranging preferably from {fraction (1/1)} to ⅓.

[0008] The term “nanoscale particles” as used in the presentspecification and in the claims is to denote particles having an averageparticle size (or an average particle diameter, respectively) of notmore than 100 nm, preferably not more than 50 nm and particularly notmore than 30 nm. According to the present invention said nanoscaleparticles preferably have an average particle size ranging from 1 to 40nm, more preferred from 3 to 30 nm, a particle size of not more than 30nm usually being a prerequisite for superparamagnetism.

[0009] It is particularly preferred for the core of the nanoscaleparticles according to the present invention to comprise(superparamagnetic) magnetite, maghemite or stoichiometric intermediateforms thereof.

[0010] The nanoscale particles according to the present inventionusually have only two shells. However, it is also possible to providemore than one outer shell, e.g., two shells constituted by differentspecies.

[0011] The exposed innermost shell (in closest proximity to the core) isa coat that is degraded at a relatively low rate by the human or animalbody tissue (particularly tumor tissue) and has cationic groups orgroups capable of forming cationic groups, respectively. Usually saidgroups consist of (positively charged) amino groups although accordingto the invention other positively charged or chargeable, respectivelygroups may be employed as well.

[0012] The cores of the nanoscale particles according to the presentinvention may be provided with the innermost shell in any manner and ina manner well known to the person skilled in the art. It must, however,be ensured that the innermost shell is degraded inside the (tumor)tissue at a rate which is sufficiently low to allow adhesion of theparticles onto the cell surface and an importation of the particles intothe cells (preferably tumor cells) and that said innermost shell hassome—preferably as many as possible—cationic groups. Normally theinnermost shell has on the average at least 50, preferably at least 100and particularly at least 500 cationic groups (e.g., positively chargedamino groups). According to a preferred embodiment of the presentinvention the coat is provided by using monomeric aminosilanes such as,e.g., 3-aminopropyltriethoxysilane,2-aminoethyl-3-aminopropyltrimethoxysilane,trimethoxysilylpropyldiethylenetriamine andN-(6-aminohexyl)-3-aminopropyltrimethoxysilane. Preferably said silanesare applied onto said cores in known manner and are than subjected topolycondensation in order to achieve high stability. A method suitablefor said purpose is described in, e.g., DE-A-19614136. The correspondingdisclosure is explicitly referred to herein. A further process suitablefor the provision, around an iron oxide-containing core, of an innermostshell having cationic groups can be taken from, e.g., DE-A-19515820.Naturally other processes may be employed for said purpose as well.

[0013] According to the present invention one or more (preferably one)outer shells are provided on the described innermost shell. In thefollowing discussion it is assumed that only one single outer shell ispresent. If more than one outer shell is desired, the additional shellsare provided in analogous manner.

[0014] As already explained, the outer shell serves to achieve a gooddistribution within the tumor tissue of the iron oxide-containing coreshaving said inner shell, said outer shell being required to bebiologically degradable (i.e., by the tissue) after having served itspurpose to expose the underlying innermost shell, which permits a smoothincorporation into the inside of the cells and an association with thesurfaces of the cells, respectively. The outer shell is constituted byspecies having no positively charged functional groups, but on thecontrary having preferably negatively charged functional groups so that,from without, said nanoscale particles appear to have an overall neutralcharge (either by virtue of a shielding (masking) of the positivecharges inside thereof and/or neutralization thereof by negative chargesas may, for example, be provided by carboxylic groups) or even anegative charge (for example due to an excess of negatively chargedgroups). According to the present invention for said purpose there maybe employed, for example, readily (rapidly) biologically degradablepolymers featuring groups suitable for coupling to the underlying shell(particularly innermost shell), e.g., (co)polymers based onα-hydroxycarboxylic acids (such as, e.g., polylactic acid, polyglycolicacid and copolymers of said acids) or polyacids (e.g., sebacic acid).The use of optionally modified, naturally occurring substances,particularly biopolymers, is particularly preferred for said purpose.Among the biopolymers the carbohydrates (sugars) and particularly thedextrans may, for example, be cited. In order to generate negativelycharged groups in said neutral molecules one may employ, for example,weak oxidants that convert part of the hydroxyl or aldehydefunctionalities into (negatively charged) carboxylic groups).

[0015] It must be emphasized, however, that in the synthesis of theouter coat one is not limited to carbohydrates or the other speciesrecited above but that on the contrary any other naturally occurring orsynthetic substances may be employed as well as long as they satisfy therequirements as to biological degradability (e.g. enzymatically) andcharge or masking of charge, respectively.

[0016] The outer layer may be coupled to the inner layer (or anunderlying layer, respectively) in a manner known to the person skilledin the art. The coupling may, for example, be of the electrostatic,covalent or coordination type. In the case of covalent interactionsthere may, for example, be employed the conventional bond-formingreactions of organic chemistry, such as, e.g., ester formation, amideformation and imine formation. It is, for example, possible to react apart of or all of the amino groups of the innermost shell withcarboxylic groups or aldehyde groups of corresponding species employedfor the synthesis of the outer shell(s), whereby said amino groups areconsumed (masked) with formation of (poly-)amides or imines. Thebiological degradation of the outer shell(s) may then be effected by(e.g., enzymatic) cleavage of said bonds, whereby at the same time saidamino groups are regenerated.

[0017] Although the essential elements of the nanoscale particlesaccording to the present invention are (i) the iron oxide-containingcore, (ii) the inner shell which in its exposed state is positivelycharged and which is degradable at a lower rate, and (iii) the outershell which is biologically degradable at a higher rate and which, fromwithout, makes the nanoscale particles appear to have an overall neutralor negative charge, the particles according to the invention still maycomprise other, additional components. In this context there mayparticularly be cited substances which by means of the particles of thepresent invention are to be imported into the inside of cells(preferably tumor cells) to enhance the effect of the cores excited byan alternating magnetic field therein or to fulfill a functionindependent thereof. Such substances are coupled to the -inner shellpreferably via covalent bonds or electrostatic interactions (preferablyprior to the synthesis of the outer shell(s)). This can be effectedaccording to the same mechanisms as in the case of attaching the outershell to the inner shell. Thus, for example in the case of usingaminosilanes as the compounds constituting the inner shell, part of theamino groups present could be employed for attaching such compounds.However, in that case there still must remain a sufficient number ofamino groups (after the degradation of the outer shell) to ensure thesmooth importation of the iron oxide-containing cores into the inside ofthe cells. Not more than 10% of the amino groups present should ingeneral be consumed for the importation of other substances into theinside of the cells. However, alternatively or cumulatively it is alsopossible to employ silanes different from aminosilanes and havingdifferent functional groups for the synthesis of the inner shell, tosubsequently utilize said different functional groups for the attachmentof other substances and/or the outer shell to the inner shell. Examplesof other functional groups are, e.g., unsaturated bonds or epoxy groupsas they are provided by, for example, silanes having (meth)acrylicgroups or epoxy groups.

[0018] According to the present invention it is particularly preferredto link to the inner shell substances which become completely effectiveonly at slightly elevated temperatures as generated by the excitation ofthe iron oxide-containing cores of the particles according to theinvention by an alternating magnetic field, such as, e.g.,thermosensitive chemotherapeutic agents (cytostatic agents,thermosensitizers such as doxorubicin, proteins, etc.). If for example athermosensitizer is coupled to the innermost shell (e.g. via aminogroups) the corresponding thermosensitizer molecules become reactiveonly after the degradation of the outer coat (e.g. of dextran) upongeneration of heat (by the alternating magnetic field).

[0019] For achieving optimum results, e.g. in tumor therapy, theexcitation frequency of the alternating magnetic field applicator mustbe tuned to the size of the nanoscale particles according to the presentinvention in order to achieve a maximum energy yield. Due to the gooddistribution of the particle suspension within the tumor tissue, spacesof only a few micrometers in length can be bridged in a so-called“bystander” effect known from gene therapy, on the one hand by thegeneration of heat and on the other hand through the effect of thethermosensitizer, especially if excited several times by the alternatingfield, with the result that eventually the entire tumor tissue becomesdestroyed.

[0020] Particles leaving the tumor tissue are transported by capillariesand the lymphatic system into the blood stream, and from there intoliver and spleen. In said organs the biogenous degradation of theparticles down to the cores (usually iron oxide and iron ions,respectively) then takes place, which cores on the one hand becomeexcreted and on the other hand also become resorbed and introduced intothe body's iron pool. Thus, if there is a time interval of at least 0.5to 2 hours between the intralesional application of magnetic fluid andthe excitation by the alternating field the surrounding environment ofthe tumor itself has “purged” itself of the magnetic particles so thatduring excitation by the alternating field indeed only the lesion, butnot the surrounding neighborhood will be heated.

[0021] In contrast to high molecular weight substances, nanoparticles donot leave the tissue into which they have been applied, but get caughtwithin the interstices of the tissue. They will get transported awayonly via vessels that have been perforated in the course of theapplication. High molecular weight substances, on the other hand, leavethe tissue already due to diffusion and tumor pressure or becomedeactivated by biodegradation. Said processes cannot take place with thenanoscale particles of the present invention since on the one hand theyare already small enough to be able to penetrate interstices of thetissue (which is not possible with particles in the μm range, forexample, liposomes) and on the other hand are larger than molecules and,therefore cannot leave the tissue through diffusion and capillarypressure. Moreover, in the absence of an alternating magnetic field, thenanoscale particles lack osmotic activity and hardly influence the tumorgrowth, which is absolutely necessary for an optimum distribution of theparticles within the tumor tissue.

[0022] If an early loading of the primary tumor is effected theparticles will be incorporated to a high extent by the tumor cells andwill later also be transferred to the daughter cells at a probability of50% via the parental cytoplasm. Thus, if also the more remotesurroundings of the tumor and known sites of metastatic spread,respectively are subjected to an alternating magnetic field individualtumor cells far remote from the primary tumor will be affected by thetreatment as well. Particularly the therapy of affected lymphatic nodescan thus be conducted more selectively than in the case of chemotherapy.Additional actions by gradients of a static magnetic field at sites ofrisk of a subsequent application of an alternating field may evenincrease the number of hits of loaded tumor cells.

[0023] As already mentioned above, thermosensitizers and/or cytostaticagents are preferably linked to the nanoscale particles according to thepresent invention (specifically the inner shell thereof). Only themagnetic coupling of the magnetic particles with the alternatingmagnetic field and the development of heat resulting therefrom bringsabout an activation or also a release of substances having cytotoxicaction that have (preferably) been linked to the particles according tothe present invention.

[0024] Due to the two-stage interlesional application a selectiveaccumulation is not necessary. Instead the exact localization of thelesion determined in the course of routine examination and thesubsequently conducted infiltration, in stereotactic manner or by meansof navigation systems (robotics), of the magnetic fluid into a targetregion of any small (or bigger) size are sufficient.

[0025] The combination with a gradient of a static magnetic fieldpermits a regioselective chemoembolization since not only thecyctostatic agent preferably present on the particles of the inventionis activated by heat but also a reversible aggregation of the particlesand, thus a selective embolization may be caused by the static field.

[0026] In addition to tumor therapy, further applications of thenanoscale particles according to the present invention (optionallywithout the outer shell(s)) are the heat-induced lysis of clottedmicrocapillaries (thrombi) of any localization in areas which are notaccessible by surgery and the successive dissolution of thrombi incoronary blood vessels. For example thrombolytic enzymes which show anup to ten-fold increase in activity under the action of heat or evenbecome reactive only on heating, respectively may for said purpose becoupled to the inner shell of the particles according to the invention.Following intraarterial puncture of the vessel in the immediate vicinityof the clogging the particles will automatically be transported to the“point of congestion” (e.g., under MRT control). A fiberopticaltemperature probe having a diameter of, e.g., 0.5 mm is introducedangiographically and the temperature is measured in the vicinity of thepoint of congestion while, again by external application of analternating magnetic field, a microregional heating and activation ofsaid proteolytic enzymes is caused. In the case of precise applicationof the magnetic fluid and of MRT control a determination of thetemperature can even be dispensed with on principle since the energyabsorption to be expected can already be estimated with relatively highaccuracy on the basis of the amount of magnetic fluid applied and theknown field strength and frequency. The field is reapplied in intervalsof about 6 to 8 hours. In the intervals of no excitation the body hasthe opportunity to partly transport away cell debris until eventually,supported by the body itself, the clogging is removed. Due to the smallsize of the particles of the invention the migration of said particlesthrough the ventricles of the heart and the blood vessels is uncritical.Eventually the particles again reach liver and spleen via RES.

[0027] Apart from classical hyperthermia at temperatures of up to 46/47°C. also a thermoablation can be conducted with the nanoscale particlesof the present invention. According to the state of the art mainlyinterstitial laser systems that are in part also used in surgery areemployed for thermoablative purposes. A big disadvantage of said methodis the high invasivity of the microcatheter-guided fiberoptical laserprovision and the hard to control expansion of the target volume. Thenanoparticles according to the present invention can be used for suchpurposes in a less traumatic way: following MRT-aided accumulation ofthe particle suspension in the target region, at higher amplitudes ofthe alternating field also temperatures above 50° C. can homogeneouslybe generated. Temperature control may, for example, also be effectedthrough an extremely thin fiberoptical probe having a diameter of lessthan 0.5 mm. The energy absorption as such is non-invasive.

1. Nanoscale particles having an iron oxide-containing core and at leasttwo shells surrounding said core, the (innermost) shell adjacent to thecore being a coat that features groups capable of forming cationicgroups and that is degraded by the human or animal body tissue at such alow rate that an association of the core surrounded by said coat withthe surfaces of cells and the incorporation of said core into the insideof cells, respectively is possible, and the outer shell(s) beingconstituted by species having neutral and/or anionic groups which, fromwithout, make the nanoscale particles appear neutral or negativelycharged and which is (are) degraded by the human or animal body tissueto expose the underlying shell(s) at a rate which is higher than thatfor the innermost shell but still low enough to ensure a sufficientdistribution of said nanoscale particles within a body tissue which hasbeen punctually infiltrated therewith.
 2. Nanoscale particles accordingto claim 1, wherein the core comprises magnetite, maghemite orstoichiometric intermediate forms thereof.
 3. Nanoscale particlesaccording to any one of claims 1 and 2, wherein the cores have anaverage particle size of 1 to 40 nm, preferably 3 to 30 nm.
 4. Nanoscaleparticles according to any one of claims 1 to 3, wherein the cores aresuperparamagnetic.
 5. Nanoscale particles according to any one of claims1 to 4, wherein said cores are surrounded by two shells.
 6. Nanoscaleparticles according to any one of claims 1 to 5, wherein the innermostshell features amino groups.
 7. Nanoscale particles according to any oneof claims 1 to 6, wherein the innermost shell is derived from(hydrolytically) polycondensable silanes, particularly aminosilanes. 8.Nanoscale particles according to any one of claims 1 to 7, wherein theinnermost shell on the average has at least 50, preferably at least 100,positively charged groups.
 9. Nanoscale particles according to any oneof claims 1 to 8, wherein the outer shell(s) comprise(s) optionallymodified, naturally occurring substances, particularly biopolymers. 10.Nanoscale particles according to any one of claims 1 to 9, wherein theouter shell(s) comprise(s) optionally modified carbohydrates,particularly dextrans.
 11. Nanoscale particles according to claim 10,wherein said carbohydrates are modified by carboxylic groups. 12.Nanoscale particles according to any one of claims 1 to 11, wherein oneor more pharmacologically active species, preferably selected from thegroup consisting of thermosensitizers and thermosensitivechemotherapeutic agents, are linked to the innermost shell.
 13. Magneticfluids for introduction into the human or animal body, containingnanoscale particles according to any one of claims 1 to
 12. 14. Use ofthe nanoscale particles according to any one of claims 1 to 12 for themanufacture of a magnetic fluid for use in tumor therapy byhyperthermia.
 15. Use of the nanoscale particles according to any one ofclaims 1 to 12 for the manufacture of a magnetic fluid for use in theheat-induced lysis of clogged microcapillaries (thrombi).
 16. Use of thenanoscale particles according to any one of claims 1 to 12 for themanufacture of a magnetic fluid for use in thermoablation.
 17. Method ofhomogeneously distributing and or locally/regionally increasing theconcentration of and/or diminishing the washout in biological tissues ofnanoscale particles or species coupled to said nanoscale particles,wherein said nanoscale particles are those according to any one ofclaims 1 to 12 and said particles are exposed to an alternating magneticfield once or several times.
 18. Process according to claim 17, whereinsaid species coupled to the nanoscale particles are selected from thegroup consisting of chemotherapeutical agents and isotopes.